Role of protein kinase C and mitochondrial permeability transition pore in the neuroprotective effect of ceramide in ischemia-induced cell death

Agudo-López, Alba; Miguel, B.G.; Fernández, Inmaculada; Martı́nez, Ana M.

doi:10.1016/j.febslet.2010.11.015

Cited by 28 publications

(22 citation statements)

References 24 publications

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“…2) result from Pb-induced MPTP opening. Moreover, mitochondrial injury can cause ROS production, while increased formation of ROS can induce the MPTP opening (Agudo-López et al 2011;Xu et al 2014). To further investigate the effect of MPTP opening on apoptosis in Pb-exposed rPT cells, translocation event of cyt-c from mitochondria to the cytosol was determined by western blot analysis (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial permeability transition and its regulatory components are implicated in apoptosis of primary cultures of rat proximal tubular cells exposed to lead

et al. 2015

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Previous studies have already demonstrated that mitochondria play a key role in Pb-induced apoptosis in primary cultures of rat proximal tubular (rPT) cells. To further clarify the underlying mechanism of Pb-induced mitochondrial apoptosis, this study was designed to investigate the role of mitochondrial permeability transition (MPT) and its regulatory components in Pb-induced apoptosis in rPT cells. Mitochondrial permeability transition pore (MPTP) opening together with disruption of mitochondrial ultrastructure, translocation of cytochrome c from mitochondria to cytoplasm and subsequent caspase-3 activation were observed in this study, suggesting that MPT is involved in Pb-induced apoptosis in rPT cells. Simultaneously, Pb-induced caspase-3 activation and apoptosis can be significantly inhibited by three MPTP inhibitors (CsA, DIDS, BA), which target different regulatory components of MPTP (Cyp-D, VDAC, ANT), respectively, demonstrating that Cyp-D, VDAC and ANT participate in MPTP regulation during lead exposure. Moreover, decreased ATP levels and increased ADP/ATP ratio induced by lead treatment can be significantly reversed by BA, indicating that Pb-mediated ANT dysfunction resulted in ATP depletion. In addition, up-regulation of VDAC-1, ANT-1 together with down-regulation of Cyp-D, VDAC-2 and ANT-2 at both the levels of transcription and translation were revealed in rPT cells under lead exposure conditions. In conclusion, Pb-mediated mitochondrial apoptosis in rPT cells is dependent on MPTP opening. Different expression levels in each isoform of three regulatory components contribute to alteration in their functions, which may promote the MPTP opening.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial permeability transition and its regulatory components are implicated in apoptosis of primary cultures of rat proximal tubular cells exposed to lead

et al. 2015

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“…Agudo-Lopez and collaborators (1) previously demonstrated that PKC activation mediates the protective actions of ceramide during ischemia through increased formation of ROS, which leads to the opening of MPTP. Opening of MPTP prevents mitochondrial Ca 2ϩ overload, mitochondrial swelling, and cell death (1). PKC-ε is one of PKC isozymes involved in stabilizing mitochondria by modifying MPTP opening (7).…”

Section: Discussionmentioning

confidence: 99%

Protein kinase C-α activation promotes recovery of mitochondrial function and cell survival following oxidant injury in renal cells

Nowak

Bakajsova

2012

American Journal of Physiology-Renal Physiology

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We demonstrated that nonselective PKC activation promotes mitochondrial function in renal proximal tubular cells (RPTC) following toxicant injury. However, the specific PKC isozyme mediating this effect is unknown. This study investigated the role of PKC-α in the recovery of mitochondrial functions in oxidant-injured RPTC. Wild-type PKC-α (wtPKC-α) and inactive PKC-α mutants were overexpressed in RPTC to selectively increase or block PKC-α activation. Oxidant (tert-butyl hydroperoxidel; TBHP) exposure activated PKC-α in RPTC but decreased PKC-α levels in mitochondria following treatment. Uncoupled and state 3 respirations and activities of complexes I and IV in TBHP-injured cells decreased to 55, 44, 49, and 65% of controls, respectively. F(0)F(1)-ATPase activity and ATP content in injured RPTC decreased to 59 and 60% of controls, respectively. Oxidant exposure increased reactive oxygen species (ROS) production by 210% and induced mitochondrial fragmentation and 52% RPTC lysis. Overexpressing wtPKC-α did not block TBHP-induced ROS production but improved respiration and complex I activity, restored complex IV and F(0)F(1)-ATPase activities, promoted recovery of ATP content, blocked mitochondrial fragmentation, and reduced RPTC lysis to 14%. In contrast, inhibiting PKC-α 1) induced mitochondrial hyperpolarization and fragmentation; 2) blocked increases in ROS production; 3) prevented recovery of respiratory complexes and F(0)F(1)-ATPase activities, respiration, and ATP content; and 4) exacerbated TBHP-induced RPTC lysis. We conclude that 1) activation of PKC-α prevents mitochondrial hyperpolarization and fragmentation, decreases cell death, and promotes recovery of mitochondrial respiration and ATP content following oxidant injury in RPTC; and 2) respiratory complexes I and IV and F(0)F(1)-ATPase are targets of active PKC-α.

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“…We determined that the activation of the δ-opioid receptor enhances PKC expression. PKC stimulation inhibits the apoptosis of different types of cells (38)(39)(40). Meanwhile, PKC also participates in the protection against hepatic ischemia reperfusion injury and is involved in the processes of cellular proliferation and apoptosis (19,41).…”

Section: Discussionmentioning

confidence: 99%

Activation of the δ-opioid receptor inhibits serum deprivation-induced apoptosis of human liver cells via the activation of PKC and the mitochondrial pathway

Wang¹

2011

Int J Mol Med

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Abstract. Apoptosis of human liver cells is commonly found in liver diseases and liver surgery and directly affects their prognosis. Recent studies have found that δ-opioid receptors, abundant in the membranes of hepatic cells, participate in the oncogenesis and progression of liver tumors, viral hepatitis, liver cirrhosis and other diseases. The purpose of this study was to analyze the effect of the activation of the δ-opioid receptor on liver cell apoptosis and explore its relationship with PKC and the mitochondrial pathway. Hepatic cells were serum-deprived to induce apoptosis in vitro. During the period of apoptosis, mitochondrial membrane potential decreased, protein levels of cytosolic cytochrome c increased and the expression of Bcl-2 decreased, indicating that apoptosis was specifically induced by the mitochondrial pathway. Importantly, activation of δ-opioid receptors reversed the apoptotic state of hepatic cells. Following δ-opioid receptor activation, the mitochondrial membrane potential remained stable, and the expression of cytosolic cytochrome c and Bax decreased. These data suggest that δ-opioid receptor activation specifically inhibits the mitochondrial apoptotic pathway. In addition, activation of the δ-opioid receptor apparently increased the levels of PKC; blocking the PKC pathway led to increased apoptosis of liver cells, which was not affected by the activation of δ-opioid receptor. Blocking the PKC pathway led to increased apoptosis of liver cells, which was associated with δ-opioid receptor activation. Therefore, the PKC pathway is involved in the anti-apoptotic effects of the δ-opioid receptor on liver cells.

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Role of protein kinase C and mitochondrial permeability transition pore in the neuroprotective effect of ceramide in ischemia-induced cell death

Cited by 28 publications

References 24 publications

Mitochondrial permeability transition and its regulatory components are implicated in apoptosis of primary cultures of rat proximal tubular cells exposed to lead

Mitochondrial permeability transition and its regulatory components are implicated in apoptosis of primary cultures of rat proximal tubular cells exposed to lead

Protein kinase C-α activation promotes recovery of mitochondrial function and cell survival following oxidant injury in renal cells

Activation of the δ-opioid receptor inhibits serum deprivation-induced apoptosis of human liver cells via the activation of PKC and the mitochondrial pathway

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